Folic acid supplementation in vitro induces cell type–specific changes in BRCA1 and BRCA 2 mRNA expression, but does not alter DNA methylation of their promoters or DNA repair

Abstract

Dietary supplementation with folic acid (FA) has been shown to induce opposing effects on cancer-related outcomes. The mechanism underlying such heterogeneity is unclear. We hypothesized that FA supplementation induces changes in breast cancer–associated (BRCA) genes 1 and 2 expression and function through altered epigenetic regulation in a cell type–dependent manner. We investigated the effect of treating normal and cancer cells with physiologically relevant FA concentrations on the mRNA and protein expression, capacity for DNA repair, and DNA methylation of BRCA1 and BRCA2. FA treatment induced dose-related increases in BRCA1 mRNA expression in HepG2, Huh-7D12, Hs578T, and JURKAT and in BRCA2 in HepG2, Hs578T, MCF7, and MDA-MB-157 cells. FA did not affect the corresponding normal cells or on any of the ovarian cell lines. Folic acid induced increased BRCA1 protein expression in Hs578T, but not HepG2 cells, whereas BRCA2 protein levels were undetectable. FA treatment did not alter DNA repair in liver-derived cells, whereas there were transient effects on breast-derived cells. There was no effect of FA treatment on BRCA1 or BRCA2 DNA methylation, although there was some variation in the methylation of specific CpG loci between some cell lines. Overall, these findings show that the effects of FA on BRCA-related outcomes differ between cells lines, but the biological consequences of induced changes in BRCA expression appear to be at most limited.